The succeeding sections will amplify specific points of this summary. However, it is worth mentioning at this point that some of the nonclassic types of neurotransmitters (e.g., neuropeptides and gaseous neurotransmitters such as nitric oxide) and the discovery of metabotropic receptors have required modifications of several aspects of this basic conception. (Whereas an ionotropic receptor usually contains the ion channel as an integral part of itself, a metabotropic receptor does not contain an ion channel but instead is coupled to a G protein that initiates second messenger cascades that can ultimately affect ion channels.) Some of the differences between classic and peptide transmitters are listed in
Table 6.1 . More details on the properties of peptide and gaseous transmitters are provided in the relevant parts of the section of this chapter, and metabotropic receptors are covered in the Receptors section.
Calcium Entry Is the Signal for Transmitter Release
Depolarization of the presynaptic membrane by the action potential causes voltage-gated Ca++ channels to open, which makes it possible for Ca++ to flow into the terminal and trigger the release of transmitter. However, Ca++ will enter the terminal only if there is a favorable electrochemical gradient to do so. Recall that it is the combination of the concentration and voltage gradients that determines the direction of ion flow through open channels. Extracellular [Ca++] is high relative to intracellular [Ca++], which favors entry into the terminal; however, during the peak of the action potential, the membrane potential is positive, and the voltage gradient opposes the entry of Ca++ because of its positive charge. Thus, at the peak of the action potential, relatively little Ca++ enters the terminal because although the membrane is highly permeable to Ca++ , the overall driving force is small. In fact, by using a voltage clamp, one can experimentally make the membrane potential positive and equal to the Nernst equilibrium potential for Ca++ . If this is done, no Ca++ will enter the terminal despite Ca++ channels being open, and as a result no transmitter is released and no postsynaptic response is observed. This voltage is known as the suppression potential. If the membrane potential is rapidly made negative again (because of either the end of the action potential or by adjusting the voltage clamp), Ca++ rushes into the terminal as a result of the large driving force (which arises instantaneously on repolarization) and the high membrane permeability to Ca++ (which remains high because it takes the Ca++ channels several milliseconds to close in response to the new membrane potential), thereby resulting in release of transmitter and a postsynaptic response (
Fig. 6.4 •Fig. 6.3 IPSPsandEPSPsrecordedwithamicroelectrodeinacatspinalmotorneuroninresponsetostimulationofappropriateperipheralafferentfibers.Fortytracesaresuperimposed.NotethattheseIPSPsarehyperpolarizing,butinsomecasesIPSPscanbedepolarizing—seetextforanexplanation.(RedrawnfromCurtisDR,EcclesJC.J Physiol 1959;145:529.)
Synaptic Vesicles and the Quantal Nature of Transmitter Release
How neurotransmitter is stored and how it is released are questions fundamental to synaptic transmission. Answering these questions began with two observations. The first was the discovery of small round or irregularly shaped organelles known as synaptic vesicles in presynaptic terminals by electron microscopy (see
Figs. 6.1B 6.2 ). The second observation came from recordings of postsynaptic responses at the neuromuscular junction. Normally an action potential in a motor neuron causes a large depolarization in the postsynaptic muscle, termed an end plate potential (EPP), which is equivalent to an EPSP in a neuron. However, under conditions of low extracellular [Ca++], the EPP amplitude is reduced (because the presynaptic Ca++ current is reduced, leading to a smaller rise in intracellular [Ca++], and transmitter release is proportional to [Ca++]). In this condition, the EPP is seen to fluctuate among discrete values (